1. Study Design Discussion The Ghost of Candidate Gene Past and the Ghost of Genome-wide Association Yet to Come Stephen S. Rich, Ph.D. Wake Forest University School of Medicine

3. Major Issues for Association Competing study designs –Candidate genes –Genome-wide Analysis methods BioinformaticsCosts Who to be genotyped and when What phenotypes

4. Motivation and Justification Two complementary motivations –Immediate genome-wide association study Identify novel regions No prior knowledge (admission of ignorance) Gene-gene interactions Gene-environment interactions –Immediate candidate gene evaluation Assumed knowledge (admission of omniscience) Gene-gene interactions Gene-environment interactions Claim: It will be as expensive to apply the 500K Affymetrix technology as to evaluate candidate genes using custom SNP chips – unless the latter is free

5. Issues Related to Analysis of Association Replication (internal) - corrects for multiple testing? Expected number of true positives across genome Both Candidate Gene and Genome-Wide Association studies can use the Law of Large Numbers to identify a meaningful proportion of variants for which you have power Power at an individual locus Power across the genome Can existing results in any study narrow the hypothesis space?

6. Discussion Points Design – best for efficiency and scientific value –Candidate genes can be chosen and investigated for a fixed cost (original CARE $8.5M) –Genome-wide association study is feasible (original CARE $2.4M) Technological advances –Cost equivalence –Timing and processing of samples –CARE candidate genes to target smaller list (700 genes/7000 SNPs) –CARE follow-up of GWA results (1000 genes/10000 SNPs) Analytically, methods largely worked out –Binning allele frequency results –Best way to pick the winners for subsequent typing –Integration of statistical results with databases Integration with other NHLBI (NIH) GWA scans

7. Discussion